Effects of Turmeric Compounds on Inflammatory & Metastatic Factors Involved in Cancer

How and Why Are Inflammatory Molecules Produced?

Arachidonic acid (AA) is a natural compound produced in our bodies. It's released by the membranes of immune system cells and injured or diseased cells. AA metabolizes into inflammatory molecules such as leukotrienes, prostaglandins, and thromboxanes. These are part of the body's acute immune system response to help heal injured or infected cells. ^{(vi.88, 92-93)}

Unhealthy Levels of Inflammatory Factors Promote Cancer

However, unregulated production of these molecules creates an unhealthy inflammatory state. Chronic inflammation leads to the development and progression of many diseases (e.g., diabetes and atherosclerosis) and aging. Activity from inflammatory enzymes such as cyclooxygenase-2 (COX-2), lipoxygenase (5-LOX), and inducible nitric oxide synthase (iNOS), as well as their inflammatory byproducts (such as PGE2) can also cause free radicals damage to DNA. This can lead to the development and growth of various types of cancer, including: ^{(vi.87-88, 92-94)}

• Breast cancer
• Colorectal cancer
• Cancer of the esophagus
• Head and neck cancer
• Lung cancer
• Pancreatic cancer
• Stomach (gastric) cancer
• Prostate cancer

Types of Cancer-Promoting Inflammatory Factors

COX enzymes: Research indicates that over-production of COX-2 is associated with carcinogenesis and cancer progression. One of the ways it promotes tumor growth is by blocking mechanisms that would normally get rid of damaged, precancerous, or malignant cells. Higher than normal levels of COX-2 are found in almost every type of cancer. Many of turmeric's compounds can inhibit COX activity, and curcumin is a particularly potent COX-2 inhibitor. ^(vi.56, 65)

LOX enzymes: LOX and molecules metabolized from them are involved in cell growth and promote metastatic activity of tumor cells. Studies show that the turmeric compound curcumin can inhibit LOX activity in several different cancers. ^(vi.56, 65)

iNOS: Inducible nitric oxide synthase is an enzyme stimulated by inflammatory cytokine proteins. It generates nitric oxide types of free radicals. Interestingly, NO serves normal functions in the body. For example, NO is produced on demand by brain cells, possibly for memory and learning activity. It only lasts for a few seconds, which prevents it from causing free radical damage. NO also acts to dilate and relax blood vessels. However, high levels of iNOS and NO are toxic, and can contribute to inflammation and cancer development. Turmeric compounds could help reduce too much iNOS. ^{(vi.56, 87, 95)}

Hyaluronidases: These are six related enzymes that degrade hyaluronic acid, chondroitin, and chondroitin sulfate — important components of the body's connective tissue. Many types of cancers have higher levels of hyaluronidase than normal — including prostate, bladder, breast, and head and neck carcinomas. ^(vi.96-98)

HYAL-1 is the most prevalent hyaluronidase enzyme abnormally elevated in cancers. It is regulated by EGR-1, a transcription factor protein that under normal conditions activates genes involved in healing wounds and blood vessels. Levels of HYAL-1 are particularly elevated in high-grade, invasive, and metastatic cancers, and are associated with a poorer prognosis. When present in tumors, it promotes: ^(vi.96-98)

• Unregulated malignant cell growth.
• Development of new blood vessels to feed the tumor.
• Invasive activity of cancer cells into muscles and blood vessels.

Cancers that do not produce HYAL-1 are more likely to act similar to benign tumors. Turmeric's curcumin compounds block hyaluronidase enzymes. Studies show curcumin also blocks EGR-1 in certain cancers, which would reduce HYAL-1. ^(vi.96-98)

Metalloproteases (MMPs). These metal ion-containing enzymes break down connective tissue. For example, MMP-2 and MMP-9 degrade the type of collagen that forms the basement membrane that separates organs. This allows cancer cells to enter the blood stream and lymph system, spreading out into the body. ^(vi.7, 89)

MMPs also promote other cancerous activity, such as: ^{(vi.7, 89, 99, 100)}

• MMP-2 helps aggressive cancers (e.g., melanoma and prostate) form a loose mesh that supports tumor growth, invasive activity, and metastasis.
• MMP-9 helps convert pre-cancerous cells to malignant ones.
• MT1-MMP and MMP-9 also promote cancer stem cells in brain, prostate, breast, and other types of tumors that are highly invasive and resistant to treatment.

TIMPs Help Regulate MMPs

Tissue inhibitors of metalloproteinases (TIMPs) are proteins that block MMP enzyme activity. Most MMPs contribute to angiogenesis and metastasis. Higher levels of certain TIMPs (e.g., TIMP-1 and TIMP-4) will reduce the risk of cancer spreading. However, high levels of TIMP-2s are associated with tumor growth, invasiveness, and metastasis. ^(vi.99)

Turmeric's curcumin compounds directly block MMP enzymes. They also indirectly control MMPs by affecting TIMPs: ^{(vi.99, 101)}

• Two less well-known curcumin compounds in turmeric, DMC and BDMC, reduce abnormally high levels of TIMP-2.
• Curcumin promotes TIMPs that block metastatic enzymes. For example, curcumin increases the low levels of TIMP-3 found in certain breast cancers that are linked to a worse prognosis.

Active Turmeric Compounds

Besides curcumin, turmeric compounds that help inhibit inflammatory enzymes involved in cancer include:

• CAFFEIC ACID (↓ LOX and MMP-9) ^{(vi.74, 78, 102)}
• EUGENOL (↓ iNOS, COX-2, LOX, TIMP-2, TNF, and MMPs) ^{(vi.74, 77-78, 103)}
• FISETIN (↓ COX-2, MMP-2, MMP-9, and PGE2) ^(vi.79, 81)
• LIMONENE (↓ iNOS and COX-2) ^(vi.56, 74)
• MYRICETIN (↓ COX-2, LOX, 5-LOX, MMP-2, and MMP-9) ^{(vi.56, 77-79)}
• QUERCETIN (↓ COX-2, iNOS, LOX, 5-LOX, MMP-2, MMP-9, and TIMP-2) ^{(vi.56, 77-79, 102)}
• ρ-COUMARIC ACID (↓ LOX) ^{(vi.74, 102)}
• RESVERATROL (↓ COX-2, iNOS, and MMP-9) ^(vi.56, 83)